The permissive role of microglia in oligodendrogenesis
09 / 2007 - 09 / 2008
Stichting MS Research
The proliferation and differentiation pattern of neural stem cells (NSC) in the brain highly depends on the cellular and molecular composition of their local environment. Recently, it has been suggested that factors released by activated microglia in the environment of NSC?s can modulate their fate. So far, it was generally believed that local inflammatory activity of microglia in the CNS had an adverse effect on neurogenesis. However, it has become clear that the role of activated microglia in NSC differentiation depends on their pro- or anti-inflammatory niche, which appears to be highly dependent on the nature and degree of the inflammatory stimulus. Stimulation of microglia with LPS or under chronic degenerative conditions clearly impairs neurogenesis of NSC?s, but activation of microglia by INF gamma (e.g. released by interacting T-cells) has been shown to stimulate neuronal differentiation of NSC?s. Moreover, activation of microglia by IL-4 appeared to promote oligodendrogenesis, presumably mediated by IGF-1, released by the IL-4 stimulated microglia. In particular this latest finding is of major interest for the development of therapies aimed to stimulate remyelination in MS lesions. The selective oligodendrogenesis-promoting activation of the microglia population in the environment of endogenous or transplanted NSC?s and/or oligodendrocyte progenitor cells (OPC?s) may significantly enhance oligodendrocyte formation and so promote the remyelination of denuded axons in MS lesions. In this proposal we aim to analyse the exact activation pattern that turn microglia into oligodendrogenesis-promoting cells inducing the survival and differentiation of resident or grafted NSC?s and OPC?s. We will use established in-vitro and in-vivo (mouse) models to elucidate the optimal microglia activation properties that support oligodendrogenesis.